Conformational Landscape of Mutations in the N-Terminus of the aβ1-42 Monomer

The only naturally occurring variant demonstrated to protect against developing Alzheimer’s disease is a hydrophilic mutation located in the N-terminus of amyloid-β (A2T). Current hypotheses regarding A2T’s protective effect are: (1) reduced processing from Aβ’s parent protein, the amyloid precursor protein (APP), and (2) differential biophysical properties compared with the wild type Aβ that affect its reactivity and clearance. Specifically, it has been shown this N-terminal modification alters conformational landscape, aggregation kinetics, aggregate morphology, and long term potentiation of Aβ_1-42. Conversely, a hydrophobic mutation (A2V) in the same position has been shown to give different results in the conformational landscape and aggregation kinetics of Aβ_1-42. Here, we perform a systematic evaluation of mutations with varying degrees of hydrophobicity and hydrophilicity to interrogate the N-terminus’ effect on the conformational landscape of the Aβ_1-42 monomer, using explicit solvent atomistic replica-exchange molecular dynamics simulations. To analyze these variants we examined contact (2D heat) maps of their conformational landscape to estimate the thermodynamic stability of the various conformations adopted by the variants. These results further implicate the importance of the N-terminus in the biophysical properties of Aβ_1-42.